Evolutionary influences on proteins

February 05, 2007

Within multi-exon genes, after introns are removed, the exons must be spliced back together. Splice-enhancer domains (exon sequences near the intron-exon boundary) help to ensure that this happens correctly. As they fall within the protein's exon, they must also code for specific amino acids. This dual functionality must impact protein evolution.

In a new study published online this week in the open-access journal PLoS Biology, Joanna Parmley, Laurence Hurst, and colleagues probed the effect of this dual functionality on protein sequence evolution. By comparing mouse and human genes, they found evidence that these regions are subject to selective pressure. Therefore, the need to conserve splice enhancers means these sequence regions evolve at a lower-than-average rate. Further, they also saw that smaller exons in which more of the nucleotides are close to an intron-exon boundary evolve more slowly.

In addition to this selection, the researchers found that the nucleotides in these regions are conserved and specific to splice enhancers. This is reflected in the resulting skew in amino acid content in the proteins in these areas. The authors conclude that the amino acid of a protein depends not only on its biological function, but also on its underlying gene structure and the presence of splice enhancers.

Protein evolution is known to be subject to other constraints: housekeeping genes with functions essential for cellular maintenance that are expressed in many tissues tend to evolve slowly, whereas nonessential genes frequently evolve more quickly. This study highlights that the proportion of a gene that falls in close proximity to an intron-exon boundary has a strong effect on the overall rate of protein evolution when compared with these other factors.

Parmley and colleagues also investigate retrotransposed genes--genes that have lost their introns. Such genes show accelerated evolution in the regions that were originally flanked by intron-exon boundaries. On losing the introns, the selection constraint has apparently been released (as splice enhancers are no longer needed). This also implies that, in the multi-exon forms of the proteins, the sequences were not optimized for their biological functions but have instead evolved a compromise sequence able to fulfill both roles.

The idea that the evolution of a gene can be so strongly influenced by something other than the biology of the protein it encodes is an intriguing one that might have consequences for gene therapy and protein engineering, as well as for our understanding of protein evolution. Further work will be required to investigate whether other features, apart from splice-enhancer regions, also influence nucleotide and amino acid use near the boundaries between coding and noncoding gene segments.
Citation: Parmley JL, Urrutia AO, Potrzebowski L, Kaessmann H, Hurst LD (2007) Splicing and the evolution of proteins in mammals. PLos Biol 5(2): e14. doi:10.1371/journal.pbio.0050014.

Laurence Hurst
University of Bath
BA2 7AY, Bath, Somerset
Bath, BA2 7AY
United Kingdom
+44 (0)1225 386424
+44 (0)1225 386779 (fax)


All works published in PLoS Biology are open access. Everything is immediately available--to read, download, redistribute, include in databases, and otherwise use--without cost to anyone, anywhere, subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.


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